The present invention relates to drug and gene delivery pertains particularly to an apparatus and method combining electroporation and iontophoresis for the transdermal delivery of genes, drugs and other molecules.
The medical community has long sought improved methods of transdermal delivery of medications, drugs and other molecules and fluids without physical penetration or invasion of the tissue surface. In the aforementioned applications there are disclosed apparatus and methods for the transdermal delivery of molecules such as drugs, immunizing agents, and genes into underlying tissue, cells, and to remote tissue.
In the second aforementioned parent application, there are disclosed methods and apparatus for the electroporation of drugs, immunizing agents, and genes into surface cells. In that application, apparatus is disclosed for delivery of a fluid medium carrying preselected molecules to a tissue surface and thereafter applying electrical signals by means of electrodes to the surface tissue. The field is applied at a predetermined strength and duration in order to make the walls of the tissue surface transiently permeable to permit the molecules to pass through the tissue surface into underlying tissue. Further electroporation can enable the molecules to enter preselected cells without damaging them. In another U.S. Pat. No. 5,304,120, entitled ELECTROPORATION METHOD AND APPARATUS FOR INSERTION OF DRUGS AND GENES INTO ENDOTHELIAL CELLS, certain methods and apparatus are disclosed for insertion of drugs and genes into endothelial cells. The teachings of these patents are incorporated herein by reference.
One difficulty with the prior apparatus is that the stratum corneum (SC) which consists of a thin layer of dead cells with a high electrical resistance presents a major obstacle to the administration of drugs and genes transdermally. This layer can be perforated by the administration of short high voltage electrical field pulses, which creates a dielectric breakdown of the stratum corneum forming pores which can allow the passage of molecules However, in order to transport molecules and solutions containing molecules through the pores, a driving force has been found to be needed. This driving force can be provided by any number of mechanisms as discussed in the aforementioned patents including iontophoresis. However the known electroporation apparatus and methods for efficient application of these principles is limited.
Among the prior art relating generally to this field is the Weaver et al. U.S. Pat. No. 5,019,034 entitled "Control of Transport of Molecules Across Tissue Using Electroporation". Weaver seeks an alternative to the traditional syringe and gun injection ot medications. He describes a proposal for using high voltage, short duration electrical pulses on the skin surface to produce electroporation of the tissue to enable drugs and medication to pass into the tissue. However, his disclosed apparatus and methods have limited effectiveness.
The co-pending parent application presents an invention designed to overcome the problems of the prior art by providing means to overcome the resistance to the administration of drugs transdermally presented by the stratum corneum. In accordance with one of the co-pending applications, drugs, immunizing agents, or genes are loaded into vesicles, the vesicles are brought into physical contact with the skin surface and a pulsed electrical field is applied between the vesicles and the tissue by means of electrodes. This forms pores at the interface of the vesicles and the stratum corneum such that the vesicles are pulled through an opening by dielectrophoretic force. While that approach is shown to be successtul to transport effective amounts of molecules of drugs and the like in or into the skin, it requires encapsulation into vesicles.
Electroporation is typically carried out by applying high voltage pulses between a pair of electrodes which are applied to the tissue surface. The voltage that must be applied in proportional to the distance between the electrodes. When the space between the electrodes is too great, the generated electric field penetrates deep into the tissue where it causes unpleasant nerve and muscle reaction.
While electroporation provides new pathways through the stratum corneum for passages of molecules, it does not provide a needed driving force. It is desirable that electroporation be combined with techniques for providing a driving force such as electro-incorporation, pressure or concentration gradient, sonophoresis or iontophoresis.
It is known that iontophoresis wherein low voltage is applied between widely spaced electrodes for a long period of time can transport charged molecules through existing pathways such as hair follicles and sweat glands. However, the volumes of molecules transported is very small, and insufficient for many applications. Combining electroporation and iontophoresis can increase the amount transported initially while the created pathways are open. However, the paths created by the electroporation stay open for a short period ot time and then close.
It is desirable that a simpler apparatus and method be available to combine both electroporation and iontophoresis without the unpleasant side effects for transport molecules through or into the stratum corneum.